The overall objective of this research proposal is the development of preclinical information for delivery of more effective oncolytic drug therapy. We propose to direct our efforts to six research goals in support of this objective. (1) The MTX-induced elevation of CdR-K activity and increased conversion of Ara-C to Ara-CTP in vitro will be correlated with the effect of MTX on the metabolism of Ara-C in vivo and with the oncolytic effectiveness of Ara-C plus MTX for treatment of L1210. (2) Elucidation of the physiologic basis for leucovorin rescue in mice after potentially lethal doses of MTX will be continued by studying the response of marrow and, if necessary, other organs to MTX and leucovorin rescue. (3) The biochemical basis for synergism between adriamycin and cyclophosphamide in the treatment of L1210 will be investigated in support of clinical studies with this combination. (4) The major toxicities that limit sequential treatment of L1210 with various 2-drug combinations will be characterized. (5) L5178Y after "delayed sequential multiple therapy" with Asp plus Ara-C, MTX plus 6-MP, and MTX plus Ara-C will be employed to study treatment of residual tumor cell populations. (6) New drugs or drug combinations will be screened against L1210 and L5178Y to provide clinical guidance on scheduling and drug interactions.